TPS6603 Background: Acute myeloid leukemia (AML) with isocitrate dehydrogenase-1 (IDH1) mutations represents a subset of up to approximately 7-14% of patients. For patients with IDH1m AML ineligible for first line intensive induction, the combination of a hypomethylating agent (HMA) and venetoclax (VEN) is a standard of care based on the VIALE-A study. In patients with IDH1m, the HMA azacitidine (AZA) plus VEN regimen leads to a complete remission (CR) plus CR with incomplete count recovery (CRi) rate of 66.7%, duration of remission (DoR) 21.9 months, and median overall survival (OS) of 15.2 months. However, one of the limiting features of HMA-VEN is myelosuppression, leading to dose delays and reductions, and adverse events (AEs) led to discontinuation in up to 30% of patients on the VIALE-A study. Approaches to increase tolerability and improve outcomes are of interest. Olutasidenib (OLU) is a potent, oral and selective small-molecule IDH1m inhibitor currently approved for relapsed/refractory AML patients with an IDH1 mutation, based on the pivotal cohort of a Phase 1/2 study. Overall, this study showed that OLU alone or in combination with AZA in patients with IDH1m AML was well-tolerated and showed meaningful clinical activity, including in those with prior VEN treatment. We hypothesize that, after achieving a response on HMA-VEN, de-escalating and switching maintenance from HMA-VEN to OLU-AZA followed by OLU monotherapy will lead to improved outcomes for patients with IDH1m AML. Methods: This multicenter investigator-initiated study through the University of California Hematologic Malignancies Consortium (UCHMC) is a phase II single-arm study evaluating the combination of OLU in combination with AZA followed by OLU monotherapy as a switch maintenance approach after HMA-VEN for patients with IDH1m AML. Key eligibility criteria include a diagnosis of IDH1m AML, achievement of CR or CRi to first-line HMA-VEN with no more than 4 cycles of HMA-VEN at the time of enrollment, IDH1m inhibitor naïve, age 18+, and performance status 0-2. The primary endpoint is treatment failure, defined as AML-related death, relapse, or treatment discontinuation due to AE within 12 months from the time of CR/CRi. Secondary endpoints include treatment-related AE, time to treatment failure, relapse-free survival, DoR, OS, and rate of allotransplant. Patients will receive OLU 150mg BID in combination with standard AZA during the first 4 cycles followed by OLU 150mg BID monotherapy until any discontinuation criteria are met. Disease assessments will be performed at baseline, following cycles 4, 8, and 12, and then as clinically indicated. The trial will enroll up to 28 patients across the UCHMC. The trial is currently enrolling. Clinicaltrials.gov ID is NCT07304011. Clinical trial information: NCT07304011 .

6523 Background: Mutations in isocitrate dehydrogenase 1 (m IDH1 ) occur in 7%-14% of patients with AML. Olutasidenib is a potent, oral small-molecule mIDH1 inhibitor that selectively inhibits IDH1 variants but preserves wild-type IDH1 function. The registrational phase 2 trial (NCT02719574) of olutasidenib in patients with relapsed/refractory (R/R) m IDH1 AML reported a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 35% and a median CR/CRh duration of 25.3 mo. This analysis examines patient, disease, and molecular characteristics of patients with a LT CR/CRh response to olutasidenib without transplant. Methods: Adults with R/R m IDH1 AML treated with olutasidenib 150 mg twice daily who had a CR/CRh and a duration of response (DOR) >12 mo were included. Overall survival (OS), DOR, event-free survival (EFS), and adverse events (AEs) were assessed. Univariate and multivariate logistic regression analyses were used to examine baseline factors that predicted DOR >12 vs ≤12 mo. Results: Of 147 evaluable patients, 51 (35%) achieved a CR/CRh; of these, 32 (63%) maintained a CR/CRh >12 mo. Excluding 6 patients who proceeded to transplant, 26 (51%) had a DOR >12 mo (Table). Among these patients at baseline, median age was 72 y; 69% were female; 73% had an R132C mutation; 12% had prior venetoclax; 88% were platelet transfusion independent (TI); 73% were red blood cell (RBC) TI. Patients had a median (range) of 2 (0, 5) comutations, most commonly DNMT3A (n=6) or NPM1 (n=5); 2 patients with NPM1 also had FLT3 mutations. Median (95% CI) time to response was 1.9 (1.0, 1.9) mo. Median OS and EFS were not reached. Estimated 48-mo OS was 74% (95% CI: 51%, 88%). Estimated 48-mo EFS was 69% (95% CI: 47%, 83%). 5 (19%) patients relapsed (including 1 after 24 mo); 10 (38%) patients were on treatment at data lock. Significant predictors of response >12 vs ≤12 mo by multivariate analysis were relapsed AML vs refractory AML (odds ratio [OR]: 0.19) and female sex (OR: 0.21). Age, number of comutations, m IDH1 variant, RTK pathway mutations, number of prior therapies, and baseline TI were not significant predictors. Common AEs were nausea (35%), increased ALT, asthenia, constipation, and cough (31% each). Common grade ≥3 AEs were increased ALT, gamma glutamyltransferase increased (19% each), and RBC count decreased (15%). 9 (35%) patients experienced grade ≥3 all-cause AEs after 12 mo (only 1 AE in >1 patient [Coronavirus infection]). Conclusions: Olutasidenib enabled LT CR/CRh in half of R/R m IDH1 AML patients with CR/CRh without transplant (longest response >54 mo). Multivariate analysis identified relapsed (vs refractory) AML and female sex but not baseline TI or molecular factors as a significant predictor of LT response with olutasidenib. Clinical trial information: NCT02719574 . Patients with LT response. DOR Group Patients, n (%) >12 mo 26 (100) >24 mo 19 (73) >36 mo 15 (58) >48 mo 5 (19)

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.

Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Adult patients with mIDH1R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Sixty-seven patients with R/R mIDH1R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54

Venetoclax plus azacitidine is recognized as standard of care for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). However, some patients may still not be treated with venetoclax combinations due to frailty concerns. We evaluated efficacy and safety of venetoclax plus azacitidine vs. placebo plus azacitidine in patients with newly diagnosed AML ineligible for IC from the phase 3 VIALE-A study (NCT02993523) and the phase 1b M14-358 study (NCT02203773), stratified by two methods to potentially assess frailty. The first method was age-based (75–79, 80–84, ≥85 years; n = 303 pooled from both studies) and the second was fitness-based using the AML composite model (AML-CM), a comorbidity-based model to estimate mortality risk (Group A, B, C; n = 380, from VIALE-A). Efficacy, including composite complete remission and overall survival, were improved with venetoclax plus azacitidine vs. placebo plus azacitidine across age and AML-CM groups. Safety was generally similar between age and AML-CM groups and no new safety signals were identified. Taken together, these data suggest that patients benefit from venetoclax plus azacitidine regardless of age or degree of frailty and the combination may be considered for patients with AML who may be deemed frail. Clinical trial information NCT02993523; NCT02203773.

We conducted a multi-center, open-label, randomized phase II study to assess the efficacy of Nivolumab as maintenance therapy for patients with AML in first complete remission (CR) or CR with incomplete hematologic recovery (CRi) who were not candidates for SCT. Patients were stratified and randomized to Observation (Obs) or Nivolumab (Nivo, 3mg/kg IV every 2 weeks for 46 doses). The primary endpoint was progression-free survival (PFS) defined as time to disease relapse or death due to any reason. Secondary endpoints included overall survival (OS), and evaluation of adverse events following Nivolumab administration. Eighty patients were enrolled with median duration of follow-up of 24 months (33 months among survivors). PFS was 13.2 months in the Nivolumab arm (95% CI: 8.5-21.8) and 10.9 months in the Observation arm (5.4-14.9 months). Overall PFS curves were not statistically significantly different ((Nivo/Obs)= 0.92; 95% CI: 0.54, 1.56; one-sided p = 0.38). The median OS was 53.9 months in the Nivolumab arm and 30.9 months in the Observation arm. Cox regression model HR (Nivo/Obs)= 0.78; 95% CI: 0.40, 1.51; p=0.23 (one-sided). There were more adverse events (AEs) of any type (regardless of attribution) on the Nivolumab arm; 27 (71%) patients on the Nivolumab arm had a grade 3 or higher AE compared to 5 patients (12%) on the Observation arm (p<0.001). Nivolumab maintenance after AML chemotherapy failed to improve the PFS and OS in this randomized Phase II study. There were increased AEs and SAEs with nivolumab, but these AEs and SAEs were expected and manageable. ClinicalTrials.gov ID NCT02275533

Abstract: IO-202 is a humanized immunoglobulin G1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin–like receptor B4 (LILRB4; ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro and in patients with leukemia. Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)–naïve CMML. IO-202 was well tolerated as monotherapy and in combination with AZA. Patients with R/R monocytic AML expressing high LILRB4 on leukemia blasts demonstrated clinical activity, including a complete response (CR) in dose escalation with IO-202 + AZA. In patients with HMA-naïve CMML, IO-202 + AZA led to a 27.8% CR rate and 66.7% overall response rate, based on the 2015 International Working Group response criteria for myelodysplastic/myeloproliferative neoplasms. All 18 efficacy-evaluable patients with HMA-naïve CMML (100%) achieved some form of investigator-assessed clinical benefit, including symptomatic improvement, a decrease in transfusions, reduced blasts and/or monocytes, and resolution of thrombocytopenia. Seven patients (38.9%) proceeded to allogeneic hematopoietic cell transplantation. Translational data suggest that efficacy favors patients with high LILRB4 expression, supporting the mechanism of action of IO-202. Overall, the data support a future pivotal study of IO-202 + AZA in patients with HMA-naïve CMML. This trial was registered at www.clinicaltrials.gov as #NCT04372433.

6546 Background: OLU and IVO are allosteric type II IDH1 inhibitors approved by the FDA and recommended by NCCN for IDH1 mut R/R AML patients based on single-arm trials. In the absence of a head-to-head trial, a MAIC was performed to estimate relative treatment effects of OLU vs. IVO in IDH1 mut R/R AML. Methods: Analyses used registrational data for OLU (Study 2102-HEM-101; N=147; individual-level data) and IVO (AG120-C-001; N=174; study-level data). A logistic propensity score model was used to estimate weights based on the first moment for Study 2102-HEM-101 patients to match AG120-C-001, including the following characteristics identified from a literature review, validated by clinical experts: number of prior systemic therapies, age, prior stem cell transplant, AML type, relapse type, cytogenetic risk, ECOG PS, and IDH1 mutation. Complete remission (CR) and CR + CR with partial hematological recovery (CRh) were summarized as odds ratios (ORs) and 95% confidence intervals (CIs). Duration of CR (DoCR), duration of CR+CRh, and OS were summarized in terms of difference in medians and 95% CIs. OS was also summarized in terms of hazard ratios (HRs) and restricted mean survival time (RMST). A simulated treatment comparison (STC) was performed as a sensitivity analysis. Results: Table 1 summarizes MAIC-adjusted estimates. Naïve and adjusted rates of CR and CR+CRh for OLU vs. IVO were comparable, but point estimates favored OLU for CR. Differences in median DoCR were not statistically significant but favored OLU over IVO. OLU had a significantly longer duration of CR+CRh than IVO. For OS, the naïve comparison suggested OLU was better than IVO (HR=0.72; 95% CI 0.55, 0.92), whereas the MAIC was uncertain but favored OLU. STC results were consistent with the MAIC. Conclusions: Naïve and adjusted rates of response for OLU vs. IVO were comparable (adjusted point estimate favored OLU for CR and IVO for CR+CRh), while a longer duration of CR+CRh was observed with OLU. Adjusted OS was similar between the two groups, although the HR favored OLU, and could not be estimated by response category given lack of patient characteristics and reduction in effective sample size (ESS). Results rely on the assumption of no unmeasured confounders which reflects a limitation of the methodology. MAIC results. Outcome OLU – adjusted (95% CI) IVO – observed (95% CI) MAIC OLU vs. IVO (95% CI) N ESS CR 27% 25% OR=1.12 (0.61, 2.08) 147 73.03 CR + CRh 29% 33% OR=0.83 (0.46, 1.50) 147 73.03 DoCR, median mos 21.3 (12.0, NE) 10.1 (6.5, 22.2) Diff=11.18 (-4.30, 22.72) 47 17.76 Duration of CR+CRh, median mos 17.5 (12.0, 29.1) 8.2 (5.6, 12.0) Diff=9.84 (3.24, 22.28) 51 21.06 OS, median mos 9.7 (5.6, 16.4) 9.0 (7.4, 10.2) HR=0.75 (0.53, 1.07) 147 73.03 OS, RMST mos 15.6 (12.1, 19.2) 12.2 (10.6, 13.9) Diff=3.39 (-0.51, 7.29) 147 73.03 N, sample size; NE, not estimable.

6514 Background: Mutations in the tumor suppressor TP53 gene are common in elderly patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and confer resistance to conventional chemotherapeutic DNA damaging agents. Venetoclax (Ven) added to the hypomethylating agents (HMA) of Decitabine or Azacitidine is the current standard of care for elderly patients with AML and is frequently used in high-risk MDS (HR-MDS). Currently approved dosing schedules of HMA/Ven rely on cytotoxicity and have not improved outcomes in the TP53 mutant population. The efficacy and tolerability of metronomic weekly dosing of Decitabine and Ven in HR-MDS and AML were previously described (Goldfinger et al, Blood 2024). Mechanistically, metronomic dosing relies on terminal differentiation, rather than cytotoxicity making it an attractive regimen for TP53 mutant MDS/AML. Methods: Patients with histologically confirmed AML or MDS and a TP53 mutation received a once-weekly dose of decitabine 0.2 mg/kg subcutaneously and one dose of Ven 400 mg on days 1, 8, 15 and 22 of a 28-day cycle. Results: Between April 2020 and January 2025, 40 patients with TP53 mutated myeloid malignancies were treated with metronomic weekly low-dose Decitabine/Ven (14 AML, 26 MDS). Twenty-four patients were followed prospectively as part of a clinical trial (NCT05184842), and 16 were treated off-trial and had data collected retrospectively. Median age at diagnosis was 76.5 years, 13 (32%) were from minority backgrounds, 28 (70%) had complex cytogenetics and 31 (82%) had biallelic TP53 mutations (median VAF 36%). All AML patients were ELN-poor risk, 21 MDS patients (82%) were R-IPSS high or very high risk. The median time on therapy was 5.8 months, with 10 (25%) patients still on therapy at time of data cut-off. Four patients in the AML and five in the MDS cohorts were not evaluable (2 withdrew consent, 1 lost to follow-up and 6 did not have a BM biopsy for evaluation). Of the evaluable AML patients, 7 (70%) achieved a complete remission (CR), 3 (30%) did not respond. In the evaluable MDS patients, 9 (43%) achieved a CR and 3 (15%) a marrow CR, 4 (19%) with stable disease, 5 (24%) with no response. Of the 26 patients who were transfusion-dependent at the start of therapy, 15 (58%) became transfusion-independent. For the entire cohort (n=40), the median overall survival (OS) was 11.3 months. For the AML and MDS cohorts, the OS was 11.6 and 9.9 months, respectively. In patients who underwent allogeneic stem cell transplant (n=6), OS was 16 months. Non-heme therapy-related adverse events of ≥ grade 3 was seen in 13 (54%) of patients. Conclusions: In this cohort, of elderly patients with poor risk TP53 mutated MDS and AML the use of a non-cytotoxic dosing schedule of Decitabine and Ven resulted in over half the patients achieving a CR and transfusion independence. The median OS of 11.3 months compares favorably to currently approved cytotoxic dosing of HMA/Ven. Clinical trial information: NCT05184842 .

Despite the use of hypomethylating agents (HMA), outcomes remain poor for patients with higher-risk myelodysplastic syndromes (HR-MDS). Ibrutinib (IBR) is a Bruton's Tyrosine Kinase (BTK) inhibitor that can exert anti-myeloblast activity through inhibition of NF-kB signaling. IBR also has immunomodulatory activity through binding to interleukin-2-inducible kinase (ITK). We conducted a multicenter Phase 1b trial (NCT02553941) to evaluate the safety, tolerability, and preliminary efficacy of the combination of IBR and azacitidine (AZA) in patients with HR-MDS. Patients received standard AZA in combination with IBR at two dose levels (DL), 420 mg (DL1) and 560 mg (DL2). Twenty-one patients were enrolled, including 17 with high- or very high-risk disease and six with prior HMA therapy. No dose-limiting toxicities were observed in the dose escalation cohorts. The most common grade 3 or higher adverse events included thrombocytopenia, neutropenia, anemia, and febrile neutropenia. Bleeding events occurred in 14 patients (67 %), with a grade 3 event in one patient. The overall response rate was 48 %, including 3 (14 %) complete remissions (CR) and 4 (19 %) marrow CR. Responses were seen in patients with TP53 mutations or deletions. CD34 positive bone marrow mononuclear cells (BMMC) BTK and peripheral blood MC (PBMC) ITK occupancy by IBR demonstrated on-target activity in relevant target cells. In patients with HR-MDS, the combination of IBR and AZA is safe, tolerable, and active, including responses in patients with TP53 aberrations and with prior HMA therapy. Further study in a larger, randomized trial is necessary to assess efficacy of this regimen for patients with HR-MDS.

6545 Background: A subset of patients (7-14%) with acute myeloid leukemia (AML) have mutations in the isocitrate dehydrogenase 1 gene (m IDH1 ). Olutasidenib (OLU), a selective, potent, oral inhibitor of mIDH1, is approved for treatment of relapsed/refractory (R/R) m IDH1 AML. Results from the phase 2 pivotal cohort (NCT02719574) demonstrated clinical efficacy and tolerability of OLU, with a complete remission/complete remission with partial hematological recovery (CR/CRh) rate of 35% for a median duration of 25.9 months. Here we evaluated the efficacy and safety of OLU in patients with R/R AML grouped by the number of prior regimens. Methods: The pivotal cohort of the phase 2 study assessed OLU 150 mg BID in adult patients and included efficacy endpoints of CR/CRh, overall response rate (ORR), duration of response (DOR), and overall survival (OS). This post hoc analysis evaluated outcomes based on when patients received OLU: after 1-2 or ≥3 prior lines of therapy. Results: There were 147 patients in the efficacy evaluable analysis set (1-2 prior regimens, n=93; ≥3 prior regimens, n=54). Median age was 72 years in patients with 1-2 prior regimens and 66.5 years in those with ≥3 prior regimens. Forty-three percent and 33% of patients had prior treatment with a hypomethylating agent, and 11% and 4% received prior venetoclax therapy (1-2 and ≥3 prior regimens groups, respectively). In patients with ≥3 prior regimens, 31% had prior hematopoietic stem cell transplantation vs none in those with 1-2 prior regimens. Those in the 1-2 prior regimens group had a higher ORR and CR/CRh rate and longer median OS, with a larger percentage of patients achieving CR, than those in the ≥3 prior regimens group (Table 1). All patients experienced ≥1 treatment-emergent adverse event (TEAE). Serious TEAEs were reported in 73% (68/93) and 77.8% (42/54) of patients in the 1-2 and ≥3 prior regimens groups, respectively, and TEAEs ≥grade 3 occurred in 89.2% (83/93) and 90.7% (49/54). The most common TEAEs included nausea, decreased red blood cell count, and fatigue. No new safety signals were identified. Conclusions: Higher response rates (including CR and CRh) and greater survival were observed in patients receiving OLU following 1-2 versus ≥3 prior treatment regimens, providing rationale for initiating OLU earlier in the R/R treatment paradigm. Clinical trial information: NCT02719574 . Efficacy of OLU stratified by number of prior regimens. 1-2 Prior Regimensn=93 ≥3 Prior Regimensn=54 ORR, n (%); 95% CI 50 (54); 43.1, 64.2 21 (39); 25.9, 53.1 DOR, median months (95% CI) 14.8 (7.4, 25.9) 16.6 (5.8, NR) CR rate, n (%); 95% CI 35 (38); (27.8, 48.3) 12 (22); (12.0, 35.6) DOR, median months (95% CI) 21.3 (12.0, NR) NR (8.7, NR) CR/CRh rate, n (%); 95% CI 38 (41); 30.8, 51.5 13 (24); 13.5, 37.6 DOR, median months (95% CI) 25.3 (12.0, NR) NR (8.7, NR) OS, median months (95% CI) 13.0 (9.3, 18.9) 8.9 (5.8, 14.9) NR, not reached.

The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).

Intensive chemotherapy (IC) combination with second- or third-generation TKI improves survival compared to non-IC with first-generation TKI. Allo-HCT was suggestive of improving RFS/OS after propensity score matching and multivariable analysis.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

6528 Background: Olutasidenib is a potent, selective, oral inhibitor of mIDH1 and is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, Phase 2, open-label, multicenter trial (NCT02719574). We report final five-year results from the pivotal cohort. Methods: In the pivotal cohort of the Phase 2 trial, patients with mIDH1 AML received olutasidenib 150mg BID. Primary endpoint was complete remission (CR) + CR with partial hematologic recovery (CRh) by modified IWG Criteria 2003. Data cutoff: May 15, 2023. Results: Baseline characteristics of 153 enrolled patients are shown in Table. Of 147 efficacy evaluable patients, CR was achieved in 32% (95% CI: 24.5, 40.2) and CR/CRh in 35% (95% CI: 27, 43; P<0.0001). Median time to CR/CRh was 1.9 mo (range: 0.9, 5.6). The median duration of CR/CRh was 25.3 mo (95% CI: 13.5, not reached), with maximum duration 54.6 mo. Overall response rate was 48% (95% CI: 40, 56.7), with median duration 15.5 mo (95% CI: 7.4, 26.2) and maximum duration 54.6 mo. Median overall survival was 11.6 mo (95%CI: 8.9, 15.5). In the 12 patients R/R to prior venetoclax, 33% achieved a CR/CRh; median duration of CR/CRh is not reached (ongoing at 54.3 months), and median overall survival is 16.2 months (95%CI: 2.6, not reached). Transfusion independence from red blood cells and platelets was achieved in 34 of 87 (39%) patients and 28 of 69 (41%) patients, respectively, who were dependent at baseline. 16 (11%) patients proceeded to stem cell transplant. The 5-year safety profile was consistent with what was previously reported. The most common AEs (% reported over 3 years and over the full 5 years) were: febrile neutropenia (22% and 22%), constipation (26% and 27%), diarrhea (20% and 21%), nausea (38% and 39%), fatigue (23% and 23%), pyrexia (24% and 24%), hypokalaemia (20% and 22%), red blood cell count decreased (26% and 26%), white blood cell count increased (25% and 25%). Differentiation syndrome was reported in 14% by Year 3, with no new events by Year 5. The safety profile was stable with long-term follow up. Conclusions: This analysis provides an additional 2 years of data beyond the results that led to FDA approval of olutasidenib. This first report of the five-year data further demonstrates the rapid and durable responses observed with olutasidenib in heavily pretreated patients with mIDH1 AML, including those R/R to prior venetoclax. Clinical trial information: NCT02719574 . [Table: see text]

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

Introduction Chronic myelomonocytic leukemia (CMML) is a rare and lethal hematological malignancy. Hypomethylating agents (HMAs), including azacitidine (AZA), are the only approved treatment for CMML, yet they offer complete remission (CR) rate of only 10%-20%, highlighting the unmet medical need. IO-202 is a humanized IgG1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4, also known as ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in leukemia patients. We hereby present the interim analysis of the Phase 1b dose expansion study of IO-202 combined with AZA for the treatment of HMA-naïve patients with CMML (NCT04372433). Methods Eligible HMA-naïve CMML patients across the US were enrolled. IO-202 was administered at 30 mg/kg IV on Day 1 and Day 15 of each 28-day cycle following a loading dose of 60 mg/kg on Cycle 1 Day 1. AZA was administered 75 mg/m2 IV or SC on Days 1-7 of each 28-day cycle. Adverse events (AEs) were graded according to the NCI CTCAE, Version 5.0. Efficacy was evaluated based on the IWG 2023 response criteria for higher-risk myelodysplastic syndromes. LILRB4 expression was assessed using multiparameter flow cytometry. Results As of July 8, 2024, 21 patients, 14 male and 7 female, were enrolled. The median age was 71 years (range 54 - 82). There were 18 CMML-1 (<10% blasts in bone marrow [BM] and <5% blasts in peripheral blood [PB]) and 3 CMML-2 (10%-19% blasts in BM and 5%-19% blasts in PB), with 11 classified as dysplastic and 10 as proliferative. The most common gene mutations were ASXL1 (62%), TET2 (38%) and CBL (24%), with RUNX1 and SRSF2 at 19% each. Five patients had prior therapies including 4 with hydroxyurea and 1 with fedratinib. Of the 21 patients, 16 experienced treatment-emergent adverse events (TEAEs) and 11 of these had treatment-related adverse events (TRAEs). Grade 3-4 TRAEs were reported in 3 patients. The most common TRAEs were infusion-related reaction (IRR, n=6), as well as anemia, platelet count decreased, pruritus, and pyrexia (n=2 each). Three patients each had 1 serious adverse event related to IO-202 as determined by investigators. All of them were Grade 2 and resolved without treatment delay, interruption, or dosage change in IO-202. No study deaths or dose limiting toxicities were reported As of April 2024, 16 of 21 patients have received at least one dose of IO-202 + AZA treatment. The remaining 5 patients were enrolled in May 2024 or later whose data are limited now but will be updated at the Annual Meeting. Of the 16, 14 were efficacy-evaluable, as 2 patients withdrew from the study without post treatment BM data. Among 13 patients with LILRB4 expression data in BM at baseline, 8 had >50% LILRB4 positive blasts. Key efficacy data are as following: The CR rate, including both CR (4) and CR equivalent (CRe, a CR classification for patients with <5% BM blasts at baseline) (4), was 57.1% (8/14).The objective response rate (ORR) was 78.6% (11/14). Three non-responders (assessed by C2D1 BM) included 2 who dropped out within 2 cycles of treatment due to an unrelated AE or hematopietic stem cell transplant (HCT), respectively, and 1 who has yet to show a response.Rapid response correlated with baseline LILRB4 expression. Seven of 8 patients with >50% LILRB4 positive blasts were responders after the first cycle (1 CR, 5 CR with limited count recovery, and 1 hematologic improvement of platelets).Response to IO-202 + AZA occurred in patients with a variety of dysplastic or proliferative status and gene mutations.Among the 14 efficacy-evaluable patients, 6 (43%) proceeded to HCT, 1 withdrew due to AEs unrelated to IO-202, and 7 remain on study (Cycles 4-12), of which 6 have achieved CR or CRe so far. Conclusions IO-202 + AZA is well tolerated, with a CR rate of 57.1% and ORR of 78.6%. Nearly half of evaluable patients (6/14) have been bridged to HCT thus far. Preliminary efficacy outcomes appear superior to AZA alone, with rapid, sustained responses to IO-202 + AZA. Translational data suggest LILRB4 expression as a biomarker for response to therapy, supporting the mechanism of action for IO-202. In light of the paucity of effective therapies for CMML, these data support a future pivotal study of IO-202 + AZA in HMA-naïve CMML.

Background Olutasidenib, a potent, selective, oral inhibitor of mIDH1, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a Phase 2 open-label trial (NCT02719574). Aims We report the five-year results from the pivotal cohort of the Phase 2 trial. Methods Patients with R/R mIDH1 AML received olutasidenib 150mg BID. Primary endpoint was complete remission (CR) + CR with partial hematologic recovery (CRh) by modified IWG Criteria 2003. Overall response rate (ORR) was CR + CRh+ CR with incomplete blood count recovery (CRi), partial remission (PR), and morphologic leukemiafree state (MLFS). Data cutoff: May 15, 2023. Results Baseline characteristics of enrolled patients (N=153) included median age 71 years (range 32—89), ECOG status of 0—1 in 82%, primary/de novo AML in 65%, refractory disease in 35%, and median time from diagnosis 12.7 months (range 0.7—152). Of 147 evaluable patients, CR was achieved in 32% and CR/CRh in 35% (95% CI: 27, 43; P<0.0001). Median time to CR/CRh was 1.9 mo (range: 0.9—5.6). The median duration of CR/CRh was 25.3 mo (95% CI: 13.5, not reached), with maximum duration 54.6 mo. ORR was 48% (95% CI: 40, 56.7), with median duration 15.5 mo (95% CI: 7.4, 26.2) and maximum duration 54.6 mo. Median overall survival was 11.6 mo. In the 12 patients R/R to prior venetoclax, 33% achieved CR/CRh; median duration of CR/CRh has not been reached, and median overall survival is 16.2 mo. Transfusion independence from red blood cells and platelets was achieved in 34/87 (39%) and 28/69 (41%) patients, respectively, who were dependent at baseline. Sixteen (11%) patients proceeded to stem cell transplant. The most common AEs were febrile neutropenia, constipation, diarrhea, nausea, fatigue, pyrexia, hypokalaemia, red blood cell count decreased, and white blood cell count increased. Differentiation syndrome (DS) was reported in 21 (14%) patients by Year 3; there were no new events of DS by Year 5. The safety profile was stable with long-term follow up. Summary/Conclusions The five-year data further demonstrates the rapid and durable responses observed with olutasidenib in heavily pretreated patients with mIDH1 AML, including those R/R to prior venetoclax. Supported by Rigel Pharmaceuticals.

Introduction: Up to 16% of patients with acute myeloid leukemia (AML) have a mutation in the isocitrate dehydrogenase 1 gene (mIDH1), which acts as an oncogenic driver of underlying leukemic disease. Inhibitors of mIDH1 provide therapeutic benefits. Olutasidenib, a potent and selective oral small-molecule mIDH1 inhibitor, selectively binds and inhibits both single and double-mutated IDH1 variants while retaining wild-type IDH1 function. In the registrational phase 2 trial (NCT02719574), olutasidenib demonstrated an overall response in 48% of patients with relapsed/refractory (R/R) AML; the median time to response was 1.9 months with a range of 0.9 to 10.2 months. The objective of this analysis was to evaluate whether time to response (TTR) impacted outcomes including overall survival (OS) in patients treated on this olutasidenib phase 2 trial. Methods: The pivotal cohort of this open-label, multicenter, registrational, global phase 2 trial enrolled adult patients (≥18 years of age) with mIDH1 R/R AML. Patients received 150 mg olutasidenib twice daily. The primary endpoint was complete remission (CR) plus CR with partial hematologic recovery (CRh) using criteria from the International Working Group in AML. Secondary endpoints included overall response rate (ORR), which was defined as CR + CRh + CR with incomplete blood count recovery (CRi), partial remission (PR), and morphologic leukemia-free state (MLFS); time to first response (TTFR); time to best response (TTBR); duration of response (DOR); and OS. Data cut-off was June 2023. Results: This analysis included 147 efficacy evaluable patients with up to five years of follow-up. The primary endpoint of CR/CRh was achieved by 35% (51/147) of patients. In these 51 patients with CR/CRh, the median TTBR was 1.9 months, and median OS was not reached (NR; 95%CI: 22.8, NR; range 6.3-57.1). TTBR was 0.9-1.9 months in 28/51 (55%) patients, with median OS of NR (95%CI: 38.1, NR). TTBR was 2.1-4.0 months in 17/51 (33%) patients, with median OS of 20.3 months (95%CI: 14.7, NR). TTBR was 4.6-5.6 months in 6/51 (12%) patients, with median OS of NR (95%CI: 19.4, NR). Among the 71 (48%) patients achieving an overall response, median TTFR was 1.9 months; median OS was 32.7 months (95%CI: 20.1, NR) and maximum OS was 57.1+ months. TTFR was 0.9-1 month in 23/71 (32%) patients, with median OS of NR (95%CI: 19.0, NR). TTFR was 1.1-1.9 months in 24/71 (34%) patients, with median OS of 22.9 months (95%CI: 12.5, NR). TTFR was 2.1 to 3.8 months in 17/71 (24%) patients, with median OS of 20.1 months (95%CI: 10.2, 31.3). TTFR was 4.6 to 10.2 months in 7/71 (10%) patients, with median OS of NR (95%CI: 23.9, NR). A Cox regression model showed no significant association between TTR and OS in the overall responders and those with a CR/CRh response. Among the 20 other responders (not CR/CRh), median TTFR was 1.9 months (range 0.9-10.2) and median survival was 13.7 months (95%CI: 6.0, 28.3). TTFR was <2.0 months in 12/20 other responders, with median survival of 11.3 months (95%CI: 4.4, NR). In the 8 other responders with TTFR >2.0 months, the median survival was 19.4 months (95%CI: 6.0, 31.3). Conclusions: These results show that while some patients with mIDH1 R/R AML achieve response to olutasidenib very quickly, other patients who continue treatment with olutasidenib achieve response at later timepoints, after up to 6 months of treatment for CR/CRh and 10 months for an overall response. These results support the prescribing information that suggests treating for at least 6 months to allow time for clinical response in patients without disease progression or unacceptable toxicity. Time to response was not associated with overall survival in the overall responders and those with a CR/CRh (Cox Model).